The present invention relates to dimeric non-azo naphthalimides, or non-azo bis-(benz[de]isoquinoline-1,3-dione) derivatives, their compositions, their preparations, and their uses. More specifically, the present invention relates to predominantly hydrophilic dimeric non-azo naphthalimides joined by a spacer moiety, their compositions, their preparations, and their uses in tissue welding.
Maintenance of close contact between opposed biological tissue surfaces is necessary for access of cellular and molecular species required for formation of new connective tissue components and is thus critical to tissue healing. Ideally, methods of maintaining close contact between healing tissue surfaces should interfere only minimally with tissue or organ function and only minimally affect the healing process itself.
In numerous surgical procedures mechanical closure, e.g. clamping or suturing with biocompatible materials, suffices for functionally adequate wound closure. However these mechanical methods of approximating and holding together wound surfaces can be contraindicated where they interfere seriously with structure or function or their presence complicates healing and restoration of tissue and organ function. For example, sutures cannot be satisfactorily used to hold together surfaces of small blood vessels with diameters 1-2 mm or less. Sutures actually impinge upon the vessel lumen and the fibrous tissue, which always forms in response to the presence of the suture material, further impinges upon the lumen, compromising blood flow.
As another example, anchoring sutures introduce frequent complications during healing of corneal implants. To perform the implant, a full-thickness, circular portion of central recipient cornea is removed using a trephine. A corresponding section of cornea is cut form the donor eye and inserted in the recipient eye and sutured in place. Sutures are left in place until sufficient healing occurs and structural integrity is restored. Sutures can be removed typically as early as 6 months or up to 2 years later.
Surgical complication can arise from the sutures themselves. First, the suture material can initiate an inflammatory response with resulting pain, irritation, and invitation to invasion by vision-impairing blood vessels. Second, suturing makes a hole in the cornea that allows entry into the cornea of infectious agents (e.g., virus) that are ordinarily kept out by the epithelium. Third, sutures do not apply perfectly even pressure along the circumference of the wound (although running sutures are better in this regard). Consequently, areas of the wound not firmly held together are susceptible to leakage of aqueous humor and epithelial downgrowth (into the incision), both serious complications. Together, the problems of inflammation, irritation, wound gape, leakage, and epithelial downgrowth pose significant clinical problems in post surgical management of corneal transplant and are frequent causes for transplant failure.
Use of sutures in affixing bone joint cartilage is precluded because of their mechanical interference with the smooth mutual sliding of cartilage surfaces important to unimpeded joint motion.
As an alternative to suturing, thermally-setting proteinaceous glues have been used with infra-red emitting laser beams to affix or weld, for example, small blood vessels, intestine, bone, and meniscal cartilage. Although mechanical affixation using this method generally has been satisfactory, tissue damaged thermally during lasing and the proteinaceous glue volume promote the formation of an increased volume of connective tissue which increased healing time and mechanically interfered with tissue function.
Different dyes have been used in classical photodynamic therapy, which superficially resembles the new invention described herein is a technique by which membrane alterations can be made in a living cell by irradiation of a compound or dye incorporated into the membrane of the cell. See, U.S. Pat. Nos. 4,613,322; 4,684,521; 4,649,151; and 4,878,891.
Non-azo naphthalimide dyes that are predominantly hydrophobic have been used to cross-link proteins and tissues. See, Lewis et al., U.S. Pat. No. 5,235,045, the entire content of which is hereby incorporated by reference. There is, however, a need for predominantly hydrophilic compounds to better weld or cross-link proteins and tissues having high proteoglycan or water content, such as meniscal cartilage, articular cartilage, and cornea. A means of affixing tissue surfaces in wound closure which results in requisite mechanical strength during healing, seals against leakage of fluid contents, minimal deformation or occlusion of tissue and tissue lumen, and healing without the formation of large volumes of associated connective tissue is needed.
According to the present invention, predominantly hydrophilic dimeric non-azo naphthalimide dyes are provided. These dyes are xe2x80x9cdimericxe2x80x9d in that they contain at least two 1,8-naphthalimide ring systems, joined by a spacer moiety or group. Each of the 1,8-naphthalimide ring system is free of an azo substituent and is also free of a nucleofuge. Further, the use of these new compounds in welding or cross-linking proteins or tissues are given.
More specifically, the present invention relates to a predominantly hydrophilic dimeric 1,8-naphthalimide compounds, having at least two 1,8-naphthalimide ring systems each having a ring nitrogen atom and each bears, at its 4-position, a heteroatomic electron-releasing group which is being characterized as having a heteroatom directly linked to the 4-position of the ring system and having at least one hydrogen directly attached to the heteroatom, such as amino nitrogen atom. Each of the 1,8-naphthalimide ring systems is free of any azo substituent and is also free of any nucleofuge. The two 1,8-naphthalimide ring systems are joined by a spacer moiety or group. The spacer moiety can join the two ring nitrogen atoms, or the two amino nitrogen atoms, or the ring nitrogen atom from one 1,8:-naphthalimide ring system and the amino nitrogen atom from the other 1,8-naphthalimide ring system. The remaining unsatisfied valences, if presence, of the ring nitrogen atoms or the amino nitrogen atoms, or all, are occupied by one or more alkyl substituents. These new naphthalimide dyes are further characterized as giving activated derivatives or species after being activated by a sufficient amount of activating agent in an environment independent of the presence or absence or oxygen.
These new non-azo 1,8-naphthalimide dyes can be activated in the simultaneous presence of an activating agent and the target tissue or protein.